CATABOLISM OF HEME

The end products of heme catabolism are bile pigments(blirubin & biliverdin)

Catabolism takes place in macrophages of reticuloendothelial system of spleen and liver.

6g of Hb is broken down per day, from which 250mg of bilirubin is formed.

BLOOD CELLS

LIVER

Bilirubin diglucuronide(water-soluble)

2 UDP-glucuronic acid

via bile duct to intestines

Stercobilin excreted in feces

Urobilinogen formed by bacteria KIDNEY

Urobilin excreted in urine

CO

Biliverdin IXα

Heme oxygenaseO2

Bilirubin (water-insoluble)

NADP+

NADPH

Biliverdinreductase

HemeGlobin

Hemoglobin

reabsorbedinto blood

Bilirubin (water-insoluble)via blood

to the liver

INTESTINE

Figure 2. Catabolism of hemoglobin

HYPERBILIRUBINEMIAS

Jaundice (icterus)

hyperbilirubinemia- causes yellow color of skin, nail beds and sclerae

- not a disease, but symptom of underlying disorders

Types of Jaundice

hemolytic jaundice- liver can handle 3000 mg bilirubin/day - normal is 300- massive hemolysis causes more than can be processed

- can’t be conjugated- increased bilirubin excreted into bile, urobilinogen is increased in blood, urine

- unconjugated bilirubin in blood increases = jaundice

obstructive jaundice- obstruction of the bile duct

- tumor or bile stones- gastrointestinal pain - nausea- pale, clay-colored stools- can lead to liver damage and increased conjugated bilirubin

Hepatocellular Jaundice- liver damage (cirrhosis or hepatitis) cause increasedbilirubin levels in blood due to decreased conjugation

- conjugated bilirubin not efficiently exported to bileso diffuses into blood

- increased urobilinogen in enterohepatic circulation- so urine is darker and stool is pale, clay-colored

- AST and ALT levels are elevated- nausea and anorexia

Types of Jaundice

Jaundice in Newborns

premature babies often accumulate bilirubin due to late onset of expression of bilirubin glucuronyltransferase

- maximum expression (adult level) at ~ 4 weeks- excess bilirubin can cause toxic encephalopathy

(kernicterus)- treated with blue fluorescent light

- converts bilirubin to more polar compound- can be excreted in bile without conjugation

Determination of bilirubin concentration

van den Bergh reaction (aqueous)- conjugated bilirubin reacts readily - direct reaction- unconjugated, hydrophobic, reacts slowly - both conjuaged and unconjugated react same in methanol - gives total bilirubin value

- subtraction of direct from total gives indirect

in normal serum - only 4% is conjugated -

SGOT, SGPT levels elevated in hepatic jaundice.ALP levels elevated in obstructive jaundiceγ-GT levels elevated in chronic alcoholics

CONGENITAL HYPERBILIRUBINEMIAS

1. CRIGLER-NAJJAR SYNDROME TYPE-IDEFECT IN CONJUGATIONENZYME DEFECT:-UDP-glucuronyltransferaseJaundice appears within 24hr. Of lifeUnconjugated bilirubin increases to more than 20mg/dl.Children die first two years of life.

2. CRIGLER-NAJJAR SYNDROME TYPE-IILess sever than type-IDefect in bilirubin conjugationBilirubin levels will be below 20mg/dl

3. GILBERT’S DISEASEIt is inherited as an autosomal dominant trait.defect is in the uptake of bilirubin, impairment in conjugation, decreased hepatic clearance of bilirubinBilirubin level around 3mg/dlIt is asymptomatic condition.

4. DUBIN JOHNSON’S SYNDROMEIt is an autosomal recessive traitDefect in excretion of conjugated bilirubin & increased conjugated bilirubin in blood.Bilirubin deposited in liver & appears black (black liver jaundice)

5. Rotor syndromeBilirubin excretion is defective, but no deposition in liver.

ACQUIRED HYPERBILIRUBINEMIAS

NEONATAL-PHYSIOLOGICAL JAUNDICE:It is caused by increased hemolysis.UDP-glucuronyl transferase activity is lowBilirubin level less than 5mg/dlIt disappears by 2nd week of life.

Table 2- Genetic Disorders of Bilirubin Metabolism

Condition Defect Bilirubin Clinical Findings

Crigler-Najjar syndrome

severely defective UDP-glucuronyltransferase

Unconjugated bilirubin ⇑⇑⇑

Profound jaundice

Gilberts syndrome

reduced activity of UDP-glucuronyltransferase

Unconjugated bilirubin ⇑

Very mild jaundice during illnesses

Dubin-Johnson syndrome

abnormal transport of conjugated bilirubin into the biliary system

Conjugated bilirubin ⇑⇑

Moderate jaundice

THAN Q